Type I interferon protects CD4 T cells from NK cell killing in a cGVHD model of SLE

Abstract

Abstract Myriad studies have linked type I interferon (IFN) to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). While increased levels of type I IFN are found in patients with SLE, and IFN blockade ameliorates disease in most mouse models of lupus, its precise roles in driving SLE pathogenesis remain largely unknown. Here, we dissected the role of type I IFN in disease development using the bm12 cGVHD model of SLE, where IAb (C57BL/6) mice develop SLE-like disease upon transfer of IAbm12 (bm12) CD4 T cells. Our data show increased serum levels of type I IFN over time, concomitant with the development of T follicular helper cells, germinal center (GC) B cells, plasmablasts, and anti-nuclear antibodies (ANA). However, these disease parameters are significantly reduced in IFN-α receptor-deficient (Ifnar−/−) recipient mice, indicating an important role for type I IFN sensing by non-T cells. Surprisingly, transfer of highly purified Ifnar−/− bm12 CD4 T cells into WT C57BL/6 hosts resulted in poor expansion of the transferred T cells, and limited development of GC B cells, plasmablasts, and ANA. Importantly, NK cell depletion restored the expansion of Ifnar−/− CD4 T cells and downstream sequelae. These findings suggest that one novel mechanism by which type I IFN contributes to autoimmune disease is by regulating the susceptibility of pathogenic CD4 T cells to NK cell killing, thus providing further rationale for the development of anti-IFNAR therapeutics for the treatment of SLE.